SULT2B1-CS-DOCK2 axis regulates effector T-cell exhaustion in HCC microenvironment

Author:

Wang Shuai1ORCID,Wang Rui1ORCID,Xu Nan1ORCID,Wei Xuyong1ORCID,Yang Yijie1ORCID,Lian Zhengxing1ORCID,Cen Beini1ORCID,Shen Chenchen1ORCID,Li Wangyao1ORCID,Wang Jianguo1ORCID,Zhang Zhensheng1ORCID,Tang Linsong1ORCID,Wei Qiang1234ORCID,Lu Di1234ORCID,Xu Xiao1234ORCID

Affiliation:

1. Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China

2. Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang Province, China

3. NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, Zhejiang Province, China

4. Institute of Organ Transplantation, Zhejiang University, Hangzhou, Zhejiang Province, China

Abstract

Background and Aims: HCC is a malignant disease. Compared with tyrosine kinase inhibitors (the classical therapy), immune checkpoint inhibitors are more effective in the treatment of HCC, despite their limited efficacy. Among these restricted factors, exhaustion of tumor-infiltrated lymphocytes, especially CD8+ T cells, is a core event. We aimed to determine the key factors contributing to CD8+ T-cell infiltration in HCC and investigate the underlying mechanisms. Approach and Results: Using machine learning and multiplex immunohistochemistry analysis, we showed that dedicator of cytokinesis protein 2 (DOCK2) was a potential indicator of infiltrated CD8+ T cells in HCC. Using RNA sequencing, flow cytometry analysis, and mouse HCC models, we demonstrated that DOCK2 inactivation accounted for infiltrated CD8+ T-cell exhaustion in tumors. Using quasi-targeted metabolomics, mass spectrum, and mass cytometry by time of flight analysis, we found that cholesterol sulfate synthesized by sulfotransferase 2B1 in tumor cells suppressed DOCK2 enzymatic activity of T cells. Through virtual screening, molecular docking simulation, and experiments validation, we demonstrated that tolazamide reversed DOCK2 inactivation-mediated CD8+ T-cell exhaustion and enhanced anti–programmed death-ligand 1 antibody+apatinib immunotherapeutic effects on HCC. Conclusions: This study indicates that DOCK2 controls CD8+ T-cell infiltration in HCC, and cholesterol sulfate synthesized by sulfotransferase 2B1 in tumor cells promotes effector T-cell exhaustion. The findings suggest that the usage of conventional drugs affects immunotherapy efficacy in HCC patients.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Hepatology

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